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FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma

ABSTRACT: FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma

PROVIDER: PRJNA778778 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16868829_1.fastq.gz	Fastqsanger.gz
	SRR16868829_2.fastq.gz	Fastqsanger.gz
	SRR16868830_1.fastq.gz	Fastqsanger.gz
	SRR16868830_2.fastq.gz	Fastqsanger.gz
	SRR16868831_1.fastq.gz	Fastqsanger.gz

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FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (scRNA-Seq)

Project description:Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in multiple types of cancer, including lung adenocarcinoma (LUAD). The lineage specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) regulate identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Foxa1/2 deletion leads to collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, that has been implicated in LUAD progression. Mechanistically, loss of FoxA1/2 leads to aberrant NKX2-1 activity and genomic localization, which inhibits tumorigenesis and drives alternative cellular identity programs associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a novel lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.

2022-06-08 | GSE188436 | GEO

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (ChIP-Seq)

2022-06-08 | GSE188434 | GEO

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (bulk RNA-Seq)

2022-06-08 | GSE188435 | GEO

FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma [single cell analysis]

Project description:Profound changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, stochastic loss of FoxA1/2 expression in NKX2-1-negative tumors is associated with keratinizing squamous differentiation. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia is sufficient for direct induction of keratinizing squamous cell carcinomas in the lung. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung adenocarcinoma in a context-specific manner.

2018-12-16 | GSE115900 | GEO

FoxA1 and FoxA2 are required for gastric differentiation in NKX2-1-negative lung adenocarcinoma [total RNA-seq analysis]

2018-12-16 | GSE115899 | GEO

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (ChIP-Seq)

Project description:FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (ChIP-Seq)

| PRJNA778783 | ENA

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (scRNA-Seq)

Project description:FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (scRNA-Seq)

| PRJNA778781 | ENA

FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (bulk RNA-Seq)

Project description:FoxA1 and FoxA2 regulate growth and cellular identity in NKX2-1-positive lung adenocarcinoma (bulk RNA-Seq)

| PRJNA778782 | ENA

FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.

Project description:Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in many cancers, including lung adenocarcinoma (LUAD). The lineage-specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) control identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Loss of FoxA1/2 leads to the collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic localization, which in turn actively inhibits tumorigenesis and drives alternative cellular identity programs that are associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.

| S-EPMC9378547 | biostudies-literature

FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [HiChIP]

Project description:The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric differentiation program. Using sequential recombination models, we find that FoxA1/2 are required for demethylation of gastric-defining genes after Nkx2-1 deletion. FoxA1 colocalizes with TET3, an enzyme that mediates DNA demethylation, in NKX2-1-negative tumors. Deletion of Foxa1/2 results in loss of TET3 occupancy at key gastric marker genes, indicating that FoxA1/2 recruit TET3 to lineage-specific sites. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of enhancers and promoters as well as their 3D interactions at gastric target genes following NKX2-1 loss. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming in NKX2-1-negative LUAD. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.

2024-09-11 | GSE247854 | GEO

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